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After 25 Years, New Ideas in the Prenatal Test Tube

Twenty-five years ago this month, Louise Brown became famous just by being born -- the first human conceived outside the body. Doctors removed a single egg from her mother's ovary, combined it with her father's sperm in a laboratory dish and, two and a half days later, placed the resulting eight-cell embryo into her mother's womb.

By today's standards, Louise Brown's conception seems rather conventional. Consider, by comparison, Lily and Max Karlin of Florham Park, N.J., who were conceived by in vitro fertilization, or I.V.F., two years ago.

Fertility drugs prompted their mother, Jamie Karlin, to grow, in a single cycle, 20 eggs large enough for her doctors to harvest. After being fertilized, 12 of them grew in culture for five full days to reach the embroyonic blastocyst stage -- still microscopic, but ready to hatch from its outer membrane with more than 100 cells.

Dr. Alan Copperman, director of reproductive endocrinology at Mount Sinai Medical Center in New York, transferred the two most promising blastocysts into Ms. Karlin's uterus. The remaining 10 were frozen, to await the time when Ms. Karlin and her husband, Jason, might want more children. Max and Lily were born in May 2002.

Blastocyst technology is hardly the only innovation. In the last 25 years, doctors have improved every aspect of in vitro fertilization, from their techniques for drawing eggs out of the ovary to the cultures they use to grow embryos in the lab.

Some of these advances have drastically improved the likelihood of success. In vitro fertilization performed with a woman's own eggs leads to a live birth more than 25 percent of the time, according to nationwide averages from 2000, the most recent data compiled by the Centers for Disease Control and Prevention. In 1988, success rates averaged only about 12 percent. Nearly 100,000 attempts in 2000 led to more than 35,000 babies, nearly 1 percent of the total number of babies born in the United States.

''If you'd told me 20 years ago that 1 percent of American babies would be born as a result of I.V.F., I would have laughed,'' said Dr. Mark Sauer, chief of reproductive endocrinology at Columbia University. ''Back then, we weren't even sure if it was worth learning I.V.F. because we weren't sure if it would ever really work.''

The technique remains an inexact science. Costs remain high -- an estimated $10,000 to $15,000 per attempt -- and are rarely covered by insurance in America, keeping the technology out of reach for many middle- and low-income families.

Twins, triplets and even higher-order multiple pregnancies are persistent problems, leading to premature deliveries, low birth weights and resulting health problems. Certain techniques appear to raise, at least slightly, the risk of congenital problems in children. And some innovations have turned out to be less useful than hoped.

Still, as conversations with a dozen leading practitioners of in vitro fertilization reveal, efforts to expand the technology and increase success rates continue.

Fertility Drugs Bypassed

One of the newest techniques is in vitro maturation, or I.V.M., which makes fertilization possible without the hormone injections that have been used to make several eggs mature in a single cycle. Doctors have found that a few days before ovulation, as many as 30 to 50 egg follicles have begun to mature. Normally, only one will fully ripen for ovulation, and the rest are lost. But if the eggs are removed before ovulation, many of them can be matured in the laboratory.

''We may be able to get about 15 of them out, and about 7 or 8 of those may mature,'' said Dr. Barry Behr, an embryologist who directs the in vitro fertilization laboratories at Stanford. ''Five or six of them may fertilize, and two or three of the embryos may be healthy.''

The maturation method may also provide a key to perfecting egg freezing, said Dr. Richard P. Marrs, medical director for California Fertility Partners in Los Angeles. In vitro practitioners have long been able to freeze embryos and achieve pregnancies by thawing and implanting them. Sperm are also relatively easy to freeze. But success in freezing eggs has been limited.

The difficulty is that in fully mature eggs the structures containing genes are spread out and ready to divide, and even a slight drop in temperature tends to shatter the chromosomes, Dr. Marrs said. Freezing follicles is easier, and theoretically, Dr. Marrs said, doctors may one day be able to use the techniques of I.V.M. to mature follicles after they are thawed.

Doctors are also working to improve the freezing of mature eggs, Dr. Marrs said, by bringing them to minus-60 degrees Celsius from room temperature in a few seconds.

Checking the Genes

Another technique designed to help more women become pregnant has been preimplantation genetic diagnosis, or P.G.D. Doctors remove a single cell from an eight-celled embryo and examine the genes it contains for any abnormalities that may lead to an unsuccessful pregnancy.

This kind of testing can be used to check for inherited conditions like Down syndrome, cystic fibrosis or inherited blood disorders. It can also be used to check for chromosomal abnormalities associated with early miscarriage. Some clinics use the procedure to look for X and Y chromosomes, to help couples determine the sex of their child.

Dr. Behr consults with a Southern California clinic that is one of the few that allows sex selection by the testing. ''The rule is, you have to have a child of the other gender before you are eligible to do it,'' he said.

But the technique is somewhat risky. Removing a cell from an embryo can, in some cases, cause its demise. ''You could kill 10 to 20 percent of embryos looking for the right ones,'' said Dr. Sauer of Columbia.

A Boost for Fathers

One of the most effective additions to in vitro fertilization has been intracytoplasmic sperm injection, or ICSI, which has been in use since 1992. A single sperm is injected into the center of an egg, making it possible for men with few sperm to become fathers.

''ICSI is the most important innovation that has revolutionized I.V.F.,'' said Dr. Zev Rosenwaks, director of the Center for Reproductive Medicine and Infertility at New York-Presbyterian Hospital. ''As much as 50 percent of infertility is due to the male.''

There are some questions about the new technique, however. Studies suggest that ICSI and in vitro fertilization are safe technologies. The world's largest such study covered nearly 1,000 children conceived through these methods in five European countries and found that the children, measured from birth to age 5, were as healthy as children conceived naturally.

But the study found that children conceived via ICSI had a somewhat higher rate of minor genital malformations. Earlier studies had found slightly increased risks of problems with imprinting of genes, a process that determines which of a pair of genes -- one from the mother or the father -- will be expressed.

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Beckwith-Wiedemann syndrome, which causes babies to be somewhat large and to have enlarged organs and an increased risk of developing certain cancers, is one of the disorders slightly more prevalent among ICSI babies.

Early Growth in the Lab

Blastocyst transfer, which requires keeping embryos in culture an extra couple of days, does not appear to confer any such risks. But it has been linked to an increase in births of identical twins.

Dr. Behr, who was one of the first to develop cultures that allowed embryos to grow to the blastocyst stage in the lab, has found that the incidence of identical twins, which is only 2 percent among regular in vitro fertilization pregnancies, is 5.6 percent among pregnancies resulting from blastocyst transfer. Dr. Marrs has observed an even higher incidence, up to 10 percent.

Dr. Marrs said he was considering transferring the blastocysts at a slightly earlier point to see if that might reduce the birth rates of identical twins.

The phenomenon is acceptable to many parents who have struggled with infertility and are relieved to find that they will have two babies at once. But for doctors, the increase in identical twins is frustrating because a major reason for doing blastocyst transfer is using fewer embryos and thus reducing multiple births.

''I'm not sure that irony is the right word,'' Dr. Copperman said, ''but you go to this procedure to eliminate the chance of triplets, and there goes one of the embryos splitting into identical twins.''

Some in vitro fertilization clinics have backed away from the practice of blastocyst transfer, because for some women, especially older ones, embryos that might lead to a successful pregnancy in the womb are unable to make it to the blast stage in a lab dish. Doctors would like to find other ways to identify the most promising embryos -- what Dr. Howard W. Jones Jr. calls ''the embryos with the white hats'' -- without growing them to the blastocyst stage. Dr. Jones, founder of the Jones Institute, was the first successful practitioner of in vitro fertilization in the United States.

One labor-intensive strategy is to examine embryos repeatedly during the first three days in culture.

Those that appear to be growing most normally turn out to have the greatest chance of leading to a successful pregnancy.

By transferring no more than two of these embryos, doctors can also reduce the chance of a multiple pregnancy.

''We really have to get control over multiple pregnancies, and we are trying,'' Dr. Marrs said. ''With twins and triplets, the risk of prematurity and abnormalities is just too high. And multiple pregnancies are harder on the mom.''

In Europe, many doctors transfer only one embryo per fertilization cycle. This strategy has been shown to be as effective as transferring more than one, as long as the couple goes through at least two cycles. American doctors say that practice is unrealistic in this country, where most insurance companies do not pay for in vitro fertilization.

A Method for Older Women

One avenue of research has all but come to a halt in the United States. The Food and Drug Administration has stepped in to regulate a new type of research involving the transfer of genetic material from one cell to another. This technology, known as nuclear transfer, is envisioned as a strategy to help women 40 and older have their own children.

The idea is to take a cell from an older woman -- a skin cell, for example -- and place it inside a younger woman's egg, which has had the original DNA removed. Theoretically, the new cell will divide to become an egg cell, genetically the same as an egg from the older woman's ovary, but encased in a more youthful package, perhaps more capable of leading to a successful pregnancy.

The technique has been used to generate eggs in animals, but it has not yet led to a successful pregnancy.

In 2001, the Food and Drug Administration sent letters to several American researchers informing them that they would have to file an Investigational New Drug, or I.N.D., application and demonstrate the safety of the technique.

Although the agency would not disclose whether any researchers had made such an application, many in vitro practitioners say they believe the effort and cost will be prohibitive.

''To file an I.N.D. for nuclear transfer would cost maybe $20 to $40 million and take 10 to 12 years,'' Dr. Marrs said.

Dr. Jacques Cohen, scientific director of assisted reproduction at St. Barnabas Medical Center in Livingston, N.J., said he was preparing to apply to the Food and Drug Administration to investigate a somewhat different strategy for helping women with persistent fertility problems.

His strategy, called cytoplasmic transfer, is to inject such a woman's egg with cytoplasm from another woman's egg. Presumably the shot of cytoplasm will confer healthful and youthful properties to help make the egg more fertile.

Dr. Cohen has already used his technique to achieve 17 pregnancies. He stopped his work in 2001, however, when the drug agency notified him that he would need its approval.

Research on the nuclear technique continues in other countries, mainly in South Korea and China.